Significantly amount of evidence suggested the central role of pancreatic beta cell dysfunction and death in the pathogenesis of type 2 diabetes mellitus (T2DM). It is hypothesized that the decreased pancreatic beta cell function and mass, a key step in the progression from metabolic impairments to a disease state, might be resulted from genetic variants. Indeed, genome-wide association studies (GWAS) have identified around 100 genes associated with T2DM, most of which pointed to beta cells. However, clarifying the biological functions and mechanism of T2DM genes identified from GWAS remains challenging, due to lacking of a robust system to systematically evaluate these variants in disease-relevant human pancreatic beta cells. Understanding the function and downstream pathways of T2DM associated genes will provide novel insight of the mechanism controlling T2DM progression. We have established a robust platform to use isogenic human embryonic stem cells (hESCs) to study the role of T2DM associated genes in human pancreatic beta cell function and survival and found that loss of CDKAL1 causes human pancreatic beta cell dysfunction and increased cell death by downregulating Metallothionein 1E (MT1E). In addition, our preliminary studies suggested that loss of SLC30A8, another T2DM associated gene, also causes human pancreatic beta cell dysfunction and downregulates MT1E. Furthermore, the forced expression of MT1E protects hESC-derived beta-like cells from high glucose and high fatty acid-induced beta cell dysfunction. Finally, the forced expression of MT1E rescues function of T2DM islets. Here, we will test the hypothesis that MT1E plays a central role to control human pancreatic beta cell function and survival. Finally, MT1E will be forced expressed in T2DM islets to rescue dysfunction and death. Together, this proposal will not only identify a novel biomarker to study the heterogeneity of human pancreatic beta cells, but also lead to the discovery of a novel target of T2DM drug development.